CN1165655A - Method of treating conditions with estrogen agonists - Google Patents

Method of treating conditions with estrogen agonists Download PDF

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CN1165655A
CN1165655A CN97103415A CN97103415A CN1165655A CN 1165655 A CN1165655 A CN 1165655A CN 97103415 A CN97103415 A CN 97103415A CN 97103415 A CN97103415 A CN 97103415A CN 1165655 A CN1165655 A CN 1165655A
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phenyl
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戴维·B·麦克莱恩
戴维·D·汤普森
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Pfizer Inc
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Abstract

Pharmaceutical compositions that comprise compounds of this formula are useful for treating or preventing Alzheimer's disease, premenstrual syndrome, perimenopausal syndrome, a deficiency of thrombomodulin, uterine fibrosis, excessive myeloproxidase activity, excessive thrombin, autoimmune disease, reperfusion damage of ischemic myocardium and insufficient testosterone.

Description

Method with treating conditions with estrogen agonists
It is reported that some estrogen agonists is suppressing because very useful aspect the disease of the relevant tract that estrogen agonists or antagonist cause.Be that the 2-phenyl-3-aroyl benzothiophene kind and 1-(alkylamino the ethoxyl phenenyl)-1-phenyl-2-phenyl but-1-ene class of representative has extensive use as the estrogen beta stimulant particularly with raloxifene and tamoxifen.
Figure A9710341500111
The raloxifene tamoxifen
Raloxifene it is said to treating following disease effective: acne, U.S.5,439,923; Baldness, EP 0659414A2; Alzheimer (Alzheimer ' Disease), EP 0659418A1; Skin and vaginal atrophy, U.S.5,461,064; Autoimmune disease, EP 0664123; Breast carcinoma, US4,418,068; Mastopathy, 0659419; Cartilage degradation, US 5,418, and 252; CNS (central nervous system) sick (after the amenorrhea), 94 EP 0309470; Endocrine Target organ disease, US 4,418, and 068; Delayed puberty, US 5,451, and 589; Demyelination; US 5,434, and 166; The myelin bone aching; US5,434,166; Dysmenorrhea, US 5,446, and 053; Endometriosis, US 5,461, and 065; Woman's acyesis, EP 659429A; The fertility disease; Hirsutism, EP 0659414, A2; Hypoglycemosia, EP635264 A2; Hyperaphrodisia, US 5,439, and 931; Fertility suppresses, and US 5,462, and 949; LDL (low density lipoprotein, LDL) oxidation, EP 0664121 A; Hypercholesterolemia, US 5,464, and 845; Lupus erythematosus, EP 0664125; Macrophage function is impaired, EP 659425 A1; Male infertility, EP 0659424A1; Myocardial infarction, ischemia, thromboembolic disorders, thunder enzyme inhibition with fixed attention, EP 0664126; The disease of menopause, EP 0659415; Menoxenia, US 5,462, and 950; Obesity, 94 EP0309481; Compulsion disease, EP 0659428; Osteoporosis, US 5,457, and 117; Ovarian agenesis, US 5,451, and 589; The amenorrhea syndrome, US 5,391, and 557; Peripheral vessel shrinks, US5,470,883; CNS disease after the amenorrhea, EP 0659415; Premenstrual syndrome, US 5,389, and 670; Carcinoma of prostate; Prostatic hyperplasia; Pulmonary hypertension, US 5,447, and 941; Perfusion infringement again, American Journal of Cardiology (J.AM.Cardiol) 25,189A (1993); Resistive tumor, EP 0652004 A1; Restenosis, US 5,462, and 937; Rheumatoid arthritis, EP 0664125; Seborrheic dermatitis, US5,439,923; The sexual function forfeiture; Sexual precosity, US 5,451,590, and thromboembolism is expressed, EP0659427; The Turners syndrome, US 5,441, and 966; Fibrosis of uterus, US 5,457, and 116; With vasodilation syndrome (after the amenorrhea), 94 EP 0309473.
Tamoxifen is widely using aspect the treatment breast carcinoma and it is reported, and is effective to treating following disease or symptom: hyperlipemia, medicine theory (Drug Ther.) 22/3,109 (1992); Ovarian cancer, oncology's magazine (J.Clin.Oncol.), 11, the No. 10,1957-68, (1993); Renal cell carcinoma, No. 56, the 670, Britain's radiological medicine magazine (Br.J.Radiol), 766-7 (1983); The inhibition of atherosclerosis factor homocysteine, Env.J.Cancer 29 bookbinding bases 6, S110 (1993); Shift melanoma, No. 12, the 8, Journal of Clinical Oncology, 1553-60 (1994); Mazalgia, No. 32, the 6, medicine (Drugs), 477-80, (1986); Prolactin antagonist secretion pituitary tumor, endocrine research magazine (J.Endrocrinol.Invest.) 3/4,343-347 (1980); Osteoporosis, american cancer research association annual meeting article (Proc.Annu Meet Am Assoc.Cancer Res.); 33:A566-7 (1992); Neural peritoneum (netroperitoneal) fibrosis, No. 341, the 8841, Lancet, 382 (1993).
The structural slight change of estrogen agonists can cause its great biological characteristics difference.For example, droloxifene (3-hydroxyl tamoxifen), following formula I is compared with tamoxifen, it have 10～60 times high with affinity estrogen receptor.Droloxifene does not have in the body or external carcinogenic or response facilitation effect, and tamoxifen causes the Hepar Mus tumor.People such as Hasmamu, cancer communication (Cancer Letter) 84,101-116 (1994).
It is reported that droloxifene is effective to treating following disease: breast carcinoma, US 5,047, and 431; Endometriosis, US 5,455, and 275; Low cholesterol, US 5,426, and 123; Osteoporosis, US5254,594; Prostatic hyperplasia, US 5,441, and 986; And restenosis, US 5,384, and 332.
The invention provides the method that a kind of inhibition is selected from following pathological symptom: syndrome before and after the Alzheimer's disease, premenstrual syndrome, amenorrhea, thrombomodulin shortage, fibrosis of uterus, excessively activity of myeloperoxidase, thrombin too much, the infringement of perfusion again and the testosterone deficiency of autoimmune disease, myocardial ischemia.This method comprises to what suffer from described pathological symptom waits to control mammal effective dose formula I chemical compound and its optics and geometric isomer; With and the acceptable acid-addition salts of nontoxic pharmacology, N-oxide, ester and quaternary ammonium salt:
Figure A9710341500131
Wherein,
A is selected from CH 2And NR;
B, D and E independently are selected from CH and N;
Y is:
(a) phenyl is chosen wantonly and independently is selected from R by 1-3 4Substituent group replace;
(b) naphthyl is chosen wantonly and independently is selected from R by 1-3 4Substituent group replace;
(c) C 3-C 8Cycloalkyl is chosen wantonly and independently is selected from R by 1-2 4Substituent group replace;
(d) C 3-C 8Cycloalkenyl group is chosen wantonly and independently is selected from R by 1-2 4Substituent group replace;
(e) five-ring heterocycles, this ring contain and are selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
(f) hexa-member heterocycle, this ring contain and are selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
(g) condense the bicyclic system that forms by one five or hexa-member heterocycle and phenyl ring, described heterocycle contains and is selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
Z 1For:
(a)-(CH 2) pW(CH 2) q-；
(b)-O(CH 2) pCR 5R 6-；
(c)-O(CH 2) pW(CH 2) q；
(d)-OCHR 2CHR 3-; Or
(e)-SCHR 2CHR 3-；
G is: (a)-and NR 7R 8(b)
Wherein, n is 0,1 or 2; M is 1,2 or 3; Z 2Be-NH-,-O-,-S-or-CH 2-; Choose wantonly on adjacent carbons and condense, choose wantonly and independently on carbon atom replaced, and choose that independence is selected from R on the N atom wantonly by 1-3 substituent group with one or two phenyl ring 4The chemical property suitable substituents replace; Or
(c) contain the Neoquess of 5～12 carbon atoms, or for bridge closes or for condensing, and optionally independently be selected from R 41～3 substituent group replace; Or
Z 1With the combination of G can be:
Figure A9710341500142
W is:
(a)-CH 2-；
(b)-CH＝CH-；
(c)-O-；
(d)-NR 2-；
(e)-S(O) n-；
(f)
Figure A9710341500143
(g)-CR 2(OH)-；
(h)-CONR 2-；
(i)-NR 2CO-; (j) Or
(k)-C ≡ C-; R is hydrogen or C 1-C 6Alkyl; R 2And R 3Independently be: (a) hydrogen; Or (b) C 1-C 4Alkyl; R 4Be: (a) hydrogen; (b) halogen; (c) C 1-C 6Alkyl; (d) C 1-C 4Alkoxyl; (e) C 1-C 4Acyloxy; (f) C 1-C 4Alkyl sulfide; (g) C 1-C 4Alkyl sulphinyl; (h) C 1-C 4Alkyl sulphonyl; (i) hydroxyl (C 1-C 4) alkyl; (j) aryl (C 1-C 4) alkyl; (k)-CO 2H; (l)-CN; (m)-CONHOR; (n)-SO 2NHR; (o)-NH 2(p) C 1-C 4Alkylamino; (q) C 1-C 4Dialkylamino; (r)-NHSO 2(s)-NO 2(t) aryl; Or
(u)-OH。
R 5And R 6Independent is C 1-C 8Alkyl or form C together 3-C 10Carbocyclic ring;
R 7And R 8Independently be:
(a) phenyl;
(b) saturated or undersaturated C 3-C 10Carbocyclic ring;
(c) contain and be selected from-O-,-N-and-S-in two heteroatomic C at the most 3-C 10Heterocycle;
(d)H；
(e) C 1-C 6Alkyl; Or
(f) and R 5Or R 6Form 3～8 yuan the azo-cycle that contains;
The R of linearity or annular form no matter 7And R 8, can independently be selected from C arbitrarily 1-C 6Three substituent groups at the most of alkyl, halogen, alkoxyl, hydroxyl and carboxyl replace;
R 7And R 8The ring that forms can be arbitrarily and phenyl ring condense;
E is 0,1 or 2;
M is 1,2 or 3;
N is 0,1 or 2;
P is 0,1,2 or 3;
Q is 0,1,2 or 3.
The preferred compound of the present invention of formula I is a following formula: Wherein, G is
Figure A9710341500162
Or With
R 4Be H, OH, F or Cl; And B and E independently are selected from CH and N.
Particularly preferred chemical compound is:
Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidines-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol;
(-)-cis-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol;
Cis-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol;
Cis-1-[6 '-pyrrolidine ethyoxyl-3 '-pyridine radicals]-2-phenyl-6-hydroxyl-1,2,3, the 4-naphthane;
1-(4 '-the pyrrolidine ethoxyphenyl)-2-(4 " fluorophenyl)-6-hydroxyl-1,2,3, the 4-tetrahydroisoquinoline;
Cis-6-(4 '-hydroxyphenyl)-5-[4-(2-piperidines-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol; With
1-(4 '-the pyrrolidinyl ethoxyphenyl)-2-phenyl-6-hydroxyl-1,2,3, the 4-tetrahydroisoquinoline.
The invention provides a kind of method that suppresses some pathological symptoms, these diseases are responsive or part sensitivity to estrogen, estrogen antagonist or estrogen antagonist.They comprise: syndrome before and after the Alzheimer's disease, premenstrual syndrome, amenorrhea, thrombomodulin shortage, fibrosis of uterus, excessively activity of myeloperoxidase, thrombin too much, the infringement of perfusion again and the testosterone deficiency of autoimmune disease, myocardial ischemia.
Alzheimer (AD) is a kind of brain degenerative disease, and Clinical symptoms shows as gradual loss of memory, discernment, the rational faculty, judgment and emotional stability, causes serious Mental Subnormality so that last dead gradually.AD is a common cause of the gradual Mental Subnormality of old people (dementia), and AD is considered to the most common medical reasons that causes death of the 4th in the U.S..Have all in the various ethnic groups in the world and race that AD is sick to be taken place, and become present and following public health problem.This disease estimates approximately to torment the independent U.S. at present just 2～3 million peoples approximately.At present, AD proves incurable disease.
AD patient's brain shows nerve degeneration and distinctive damage, and the latter refers to plaque, blood vessel amyloidosis angiopathy and the neurofibril snarling of various amyloidosis.A large amount of this class damage, the especially plaque of amyloidosis and neurofibril snarling, general many zones in AD patient's brain are found, and these zones are very important to memory and recognition function.In not suffering from most elderly brains of clinical AD, found this damage of the more restricted anatomic distribution of fewer purpose.The feature of amyloidosis plaque and blood vessel amyloidosis angiopathy also shows as the heritability cerebral hemorrhage that has trisomy (Trisomy) 21 (Down syndrome) in the individual brain and have the amyloidosis of Dutch type (HCHWA-D).At present, need in dying from this sick patient's cerebral tissue, find aforementioned damage, perhaps rarely, find in the little biopsy sample of the cerebral tissue that in invasive brain operation process, takes out making a definite diagnosis usually of AD.
Many evidences show, specific amyloidosis albumen, i.e. beta amyloid Denatured protein (β AP), gradual brain deposition, in the pathogeny of AD, have the effect of seed.Referring to Selkoe, (1991) Neuror (neuron) 6:487.Recently, shown that the neuronal cell of growing in the culture discharges β AP, and in normal person and AD patient's cerebrospinal fluid, all existed.People such as ginseng Seubert, (1992) nature (Nature) 359:325-327.
Several groups (test) confirmed that one of plaque pathology may correlative factor be the neuronic direct neural toxicity of β AP to cultivating.Reported the neurotoxicity that can reduce β AP recently with the common treatment of TGF-β.(people such as Chao, summary (Soc.Neurosci.Abs.) 19:1251 (1993) of Society for Neuroscience).
Recently, except direct neural toxicity, the inflammatory reaction in the AD brain that may be caused by β AP also has effect to this sick pathology.The restricted clinical trial of NSAID indomethacin has shown the process (people such as Rogers, science (Science) 260:1719-1720 (1993)) that can slow down Alzheimer disease.European patent application 0659418A1 discloses and has used some benzothiophene to suppress AD.
Though the research to AD mechanism makes progress to some extent, but still need exploitation treatment this sick compositions and method.Therapeutic Method should be preferably based on can increase the medicine that TGF-β expresses in the brain, therefore can alleviate the neurotoxicity and the inflammatory reaction of the beta amyloid denatured polypeptide mediation relevant with AD.
The menstruation of every month is arrived a few days ago, the get muddled symptom of emotion and inappetence of millions of improper women, these symptoms are surprising similar to the patient symptom of suffering from seasonal disorder of affect (SAD), the voracious mutation of the fat or non-anorexia of carbohydrate natural inclination.R.T.Frank claimed these syndromes to be " premenstrual tension " in 1931, and was a kind of common phenomenon.According to the Guy Abraham of UCLA, among per 10 patients that carry out gynecological's outpatient service, suffer from premenstrual tensions for 3 or 4, some people's symptom is so serious so that suicidal impulse arranged.(obstetrics and gynecology latest developments (Current Progress in Obstetrics andGynecology), 3:5-39 (1980)).
The home record of premenstrual syndrome (PMS) concentrates on getting in touch with of it and nervous, headache and weight increase.Originally observed weight increase is the reservation owing to excess salt and water, and these take place on one's body really PMS patient.But very fast proof, PMS patient also is one of them reason to the serious hope of carbohydrate (especially sweetish) and the extensive tendency of excessive absorption.PMS is also referred to as corpus luteum stage later stage syndrome (or the later stage disorder of corpus luteum stage) at present.(DNS, III, revised edition, American Psychiatric Association (American Psychiatric Association), 1987).
Etiology about PMS has many sayings.For example, some people supposes that it is caused by metrotoxin.Some people thinks because to consume sweet food too much, causes the hyperinsulinism secretion, blood glucose is too low and cerebrose is not enough, thereby causes common depressed and anxiety.Also have hypothesis to think, tissue edema causes symptom in the behavior and menstrual discomfort to cause losing and the complicated sense of society and cause mental change.
But these theories are had not a leg to stand on: hysterectomy postoperative PMS still exists, so metrotoxin is not the cause of disease; The hyperinsulinism of PMS and hypoglycemia do not have yet gets in touch, and might be the result of dystropy (that is, select the tendency of high carbohydrate meals through preceding women, this can promote insulin secretion) but not reason; The emotion of PMS and appetite variation there is no too greatly with tissue edema gets in touch; The inhuman primate that has probably no Spirit of Man power or social complexity also shows characteristic behavior and changes before warp.
Propose to overcome or reduce the PMS symptom with many methods.These comprise: sugar-free diet, the no vitamin of benefit, ovarian hormone, antidote, ovary and hypophysis irradiation and use diuretic.But these methods all only obtain limited success.
Corpus luteum stage later stage disorder (LLPDD) is present and the related term of PMS.It is relevant with the moment of menstrual cycle with mental change that many women praise many physiology.To these women of great majority, change not too serious, cause less dejected and society and occupational function do not exerted an influence.By contrast, the basic feature of LLPDD is last some all and the follicle stage begins alleviation in back several days clinical tangible emotion and behavior symptoms that occur in the corpus luteum stage.In most women, these symptoms ease after several days in menstruation arriving generation the last week and in the menstruation arriving.
Only be severe enough under the situation that the obvious damage that causes society or occupational function and most of menstrual cycle in the previous year all take place, just be diagnosed as LLPDD in symptom.
The symptom of normal experience is, significantly mood disorders (for example, shed tears suddenly, sadness or irritability outbreak), irritability feel lastingly, angry or nervous, depression and the thought of feeling oneself inferior.Also commonly the reduction of daily routines interest, subjective sensation, appetite tired and unable, that can not focus one's attention on are changed, want to eat some food (especially sugar) and sleeping eyes disorder.Also have other physiological signs, for example breast is soft or breast expands, headache, joint and myalgia, swelling sense and weight increase.
Generally, nonsteroidal antibiotic medicine is used for delivering medicine to patient LLPDD, but this is effective to some physiological signs.If the physiological signs of PMS is serious, can be according to symptom treatment.Water keeps and can be alleviated by diet and antidiuretic, but the order of severity that water keeps is not total relevant with mental symptoms.Current research shows, (the chloroxoquinoline pain may be effective alleviating dejected and crying bitterly aspect the outbreak Searle) to spironolactone.
To other medicines, comprise progesterone, lithium carbonate, thiazide, diuretic, anti-dejected medicine and bromocyptome (Parlodel R, the mountain pass scholar) also carry out overtesting, but not success.
United States Patent (USP) 5,389,670 have put down in writing with some benzothiophene treatment LLPDD/PMS.
In view of the defective and the deficiency of the existing method for the treatment of PMS/LLPDD, need new therapy.
Term " amenorrhea before and after " refers in women's life (reproduction age) before amenorrhea that time to the amenorrhea.This time period was generally 40～60 years old, but more was before and after 50 years old several years.Feature during this is that the estrogen balance changes rapidly.Though many different hormones all change during this period fast, the most attractive is property relevant hormone, particularly estrogen and (than low degree) progesterone.The cause of this variation is the nature of ovarian function and the termination of time decision.Before and after the amenorrhea after the termination of phase and the amenorrhea sign of the beginning in period be that ovarian function stops or it can not regulate over the normal ovulatory cycle of women.The clinical manifestation that this function stops is 1 year or the termination of menstruation for more time.(be amenorrhea before and after phase) during this period, ovarian function continue to end, but not burst or incident fast.The sustainable about some months of state before and after the amenorrhea was to more generally 1 year or longer.
As previously mentioned, be characterized by the variation that women's gonadal hormone is formed before and after the amenorrhea, and this variation have many sequela.Sometimes these symptoms do not have too big problem just to pass by to the women, and still, they often are the medium reasons that does not accommodate anxiety to the order of severity, and also are a reason of pathology or fatal event occasionally.
Sequela before and after these amenorrheas has defined this syndrome just.Though have very much specificity, enter the common sequela that the phase causes before and after the amenorrhea and comprise: hot secretions and antiperspirant, vaginal atrophy, headache, dizziness, absent minded, irritability, lose libido, arthralgia, insomnia, cold and detached, asthenia, muscle weakness and cardiopalmus.(" amenorrhea " (" The Menopause ") edited Park university press,, 11 chapters in 1976 by R.J.Beard).In addition, be described to the depression of " syndrome before and after amenorrhea or the amenorrhea " feature in addition.Though whether about this is that real psychosyndrome exists arguement, but before and after the amenorrhea is a factor, (" internal medicine Harrisor ' s principle " (" and Harrison ' s principles of InternalMedicine "), people such as editor N.J.Isselbacher, the 9th edition, McGraw-Hill books company, 1980, the 1782-1783 page or leaf).In extreme example, some sequela of some women be pathology (for example, liquid keeps and is unbalance) and even fatal, particularly those are to the dejected women who influences in advance.But for most women, the main cause that does not accommodate anxiety does not lie in the generation of one or more these incidents, and is time that they must stand and their not intellectual.
Have no reason to believe that any treatment can reverse old and feeble process, so can only be to alleviate character to the clinical treatment method of the syndrome before and after the amenorrhea.Particularly, amenorrhea front and back women to be controlled adopts external estrogen gradually to fall the scheme treatment.Though external estrogen can effectively be treated the symptom before and after the amenorrhea, it can not stop must to fail of ovarian function, therefore only has the effect that makes patient slowly enter amenorrhea later stage state.Thisly fall gradually that therapy often needs longer a period of time (extreme case was assigned several years) so that before ending external estrogen, ovarian function stops.Though this therapy is effective and approved, it all brings many side effect.
The side effect that estrin treatment is correlated with is not only because of estrogen, also because the progesterone that accompanies.In most cases, there is the women in uterus simultaneously or to take recycle scheme ground more frequently, gives estrogen and progesterone.The reason of administration is to reduce the danger of carcinoma of endometrium altogether, and this cancer takes place when individually dosed estrogen easily.Many women can't bear to stand the effect of progesterone, cause depression or even have offset estrogenic beneficial effect.Estrogen itself often causes offending side effect, for example water reservation, weightening finish, hypertonicity etc.The result often is that patient mismatches treatment, and continues to suffer from the symptom of amenorrhea front and back.
Ideally, the medicine of improvement should be alleviated the symptom of amenorrhea front and back syndrome, but still can avoid or reduce side effect.In addition, this ideal therapy time that can make the women enter state after the stable amenorrhea shortens.United States Patent (USP) 5,391,557 have put down in writing the treatment of amenorrhea front and back syndromes, comprise the administration benzothienyl compounds.
The blood coagulation process, promptly thrombosis is because complicated albuminolysis series connection causes the formation of thrombin.Thrombin is removed bioactive peptide on Fibrinogen A α and the B β chain in protelytic mode, and this peptide dissolves in blood plasma, therefore begins to form insoluble fibrin.
Present anticoagulant is taked administration heparin and coumarin admittedly and is finished.To solidify with thrombotic non-intestinal medicine control be by using heparin to suppress thrombosis.Heparin passes through to quicken the inhibitory action indirect action of endogenous antithrombotic III (main thrombosis physiological inhibitor) in thrombosis.Because antithrombotic III content in blood plasma differs and the surface combination effect of thrombosis makes it have resistance to this indirect action, heparin fails to become effective therapy.Be considered to relevant because some solidifies to analyze, generally monitor heparin content (especially the activated partial Thromboplastin time (APTT) is analyzed) with solidifying to analyze with efficient and safety.Coumarin hinders thrombosis to generate by blocking-up back transformation γ-carboxylated finishing when synthetic thrombinogen and other such protein.Because their mechanism of action, coumarin take effect very slow, greatly about injecting back 6-24 hour.In addition, they are not the selectivity anticoagulants.Coumarin also needs to solidify to analyze monitors (particularly Thromboplastin time series analysis).
For better understanding the present invention, below briefly introduce the thrombin system.Coagulation system claims " series connection (cascade) " sometimes, can be regarded as relate to proenzyme continuously activation be the chain reaction of active ser protease, finally cause the generation of thrombin.Thrombin is converted into not colloidal sol-fibrin by limited proteolysis with plasma fibrinogen.Solidifying has two important steps in the series connection, transform coagulation factor X to Xa and transform thrombinogen to thrombin by coagulation factor Xa by coagulation factor IXa.
These two reactions all occur in cell surface, the most important thing is at the platelet endothelial cell surface, and two reactions all need cofactor.Main cofactor V and VIII circulate as nonactive relatively precursor, but after more initial thrombin molecules formed, thrombin activated cofactor by limited proteolysis.The cofactor Va and the VIIIa that are activated have quickened thrombinogen to the conversion of thrombin and the factor X conversion to factor Xa with the multiple of about three orders of magnitude.
Activation of protein C highly selects two kinds of plasma protein substrates, its hydrolyzable and irreversibly damage this two kinds of plasma protein substrates.These plasma protein substrates are activated form of coagulation factor V and VIII (being respectively cofactor Va and VIIIa).Activation of protein C is degrade nonactive precursor, coagulation factor V and VIII of bottom line.Show the hurried circulation composition that increases major physiological fibrinoclase-tissue fibrin's dissolving proenzyme activator of activated protein C on one's body Canis familiaris L..
But activation of protein C relates to and is solidifying placed in-line final serine protease-thrombin, the glycoprotein-thrombomodulin relevant with endothelial cell membrane (thrombomodulin).Thrombomodulin forms complex with strict stoichiometric proportion 1: 1 and thrombin.When thrombomodulin and thrombin complexation, adjusted the functional character of thrombin in essence.On the passage that condenses, the general coagulating fibre proteinogen of thrombin, activated blood platelet, and will condense cofactor V and VIII be converted into their activated form.But independent thrombin activation of protein C, but just very slowly and efficient low.By contrast, forming in 1: 1 the complex with thrombomodulin, thrombin just can not the coagulating fibre proteinogen, can not activated blood platelet, condense cofactor V and VIII can not be converted into their activated form.Thrombin: the complex of thrombomodulin promotes the activation of protein C, wherein thrombin: the complex of thrombomodulin is compared with the speed constant of independent thrombin to protein C priming reaction speed constant, exceeds about 20,000 times.
Therefore, compare with other anticoagulant, for example anticoagulant such as the warfarin of heparin and oral Hydroxycoumarin type, activation of protein C has the extensively anticoagulant of therapeutic domain.Remove non local generation thrombin, protein C or activation of protein C can be ineffective.Do not have the activated by thrombin protein C with regard to non-activity, this is because need thrombin that coagulation factor V conversion Va and VIII are converted into VIIIa.The activated form that has been noted that these two cofactors is the preferred substrate of activation of protein C.The protein C proenzyme still kept the non-activity state in the past in thrombin generation after injecting patient.Do not have thrombomodulin: the thrombin complex, the protein C proenzyme is converted into reactive protein C with slow rate very.
United States Patent (USP) 5,476,862 have put down in writing the expression of adopting some benzothienyl compounds to promote thrombomodulin.
Fibrosis of uterus is a secular and present clinical problem that still exists, and it has many titles, comprising: metrauxe, myometrium hypertrophy, fibrosis of uterus and fibrosis metritis.Fibrosis of uterus is that a kind of fibrous tissue abnormal deposition is in the symptom of Uterus wall basically.
This disease can cause dysmenorrhes and sterile.Also not exclusively understand the accurate reason of this disease, but evidence suggests that this is because fibrous tissue reacts estrogen is uncomfortable.Injecting estrogen every day for Mus also had this symptom to occur in three months.On one's body the guinea pig, inject estrogen every day and also occurred this disease in 4 months.Produce same loose disease on one's body Mus in addition.
The common therapy of fibrosis of uterus adopts operation, but this is very expensive and cause some troubles, for example generation of abdominal part adhesion and infection sometimes.To some patient, first stage operation is temporary transient therapy, and the fiber-like tissue can regeneration.In those cases, stopped fibrosis and also made the women 's fertility Disability though use uterectomy.The promoting sexual gland hormone of releasing hormone antagonist is injectable also, but because of it can cause osteoporosis their use is restricted.
United States Patent (USP) 5,457,116 have put down in writing the method that suppresses fibrosis of uterus with some benzothiophene.
Autoimmune disease relates to cell and regulates immune unusual adjusting and often relevant with the macrophage effector functions with T cell, the B cell of unusual or too high adjusting autoantigen with body fluid.These cell component are relevant to the destruction that the activation of autoantigen is considered to the feedback mechanism relevant with relating to self tolerance.Autoimmune disease comprises a whole set of clinical disease kind, although the Target organ difference, they also have similarity.The women suffered from this disease and accounted for overwhelming majority reproduction age, and women male ratio is hashimoto struma 50: 1, and penetrating property lupus erythematosus (SLE) is 10: 1 entirely, myasthenia gravis 2: 1 (people such as Ahmed, U.S.'s pathology magazine (Am.J.Path.), 121:53l (1985)).In addition, this causes that disease all has following feature: chronic, clinical remission is inclined to and is known the outbreak of reason ground and relate to other organ.Although autoantibody occurs, the antigenic improper expression of II type, it is autoimmune disease basically that macrophage activation and T cellular infiltration go into that Target organ all is considered to, and the mechanism of seizure of disease and progress are not all recognized well.Therefore, to these treatment of diseases and unsatisfactory, it also relates to uses golden salt, methotrexate, antimalarial, glucocorticoid (methylprednisolone) and other immunosuppressant, and plasmapheresis with attempt to cause toleration.In past 10 years, autoimmune disease does not obtain major progress, and it is relevant mainly to be to use on-steroidal and steroid antibiotic medicine to treat this sick symptom.Clearly when must carry out the inhibition of specific immune reaction to the host time, the immunosuppressant that generalizes with glucocorticoid has side reaction tendency and immunosuppressant patient to have other infection of trouble or the non-tendency that catches of bigger danger.
Polymorphonuclear leukocyte (PMNL) plays a moderator's role in inflammation.When these cells are activated, synthesize and discharge molecule, chemical attractant and the hydrolytic enzyme at oxygen center.This proof oxygen central atom is for example played the part of decisive role in the diseases such as chronic inflammatory disease, rheumatoid arthritis, SLE at numerous disease.In the autoimmune case, SLE for example, bringing out of inflammatory reaction is antigenic stimulus patient's neutrophilic leukocyte or PMNL secretion strong oxidizer, cell and tissue around these strong oxidizers destroy.
Though estrogen in the progress of autoimmune disease and the role in degenerating very complicated and depend on the character of disease, as if it be related with autoimmune disease.As if for example estrogen can alleviate rheumatoid arthritis, but worsened systemic lupus erythematosus (Charder ﹠amp; Spector, atrophic diseases annual report (Ann Rheum.Dis.), 50:139).As Jansson report (Free Rad Res.Comms.), 14 (3), 195-208, (1991) are incorporated herein for referencial use), estrogen has strengthened a kind of enzyme that is generated by PMNL, bone marrow peroxidase, and this enzyme is regulated hydrogen peroxide and is generated oxidant.This enzyme makes hydrogen peroxide be converted into strong oxidizer and crosses chloric acid.By improving the activity of enzyme, can generate chloric acid, increased the Oxidation on chronic chronic inflammatory disease/autoimmune disease patient's tissue, cell and various macromole like this.
EP 664 125 A1 have reported and have used some 3-aroyl benzothiophene treatment can suppress the bone marrow peroxidase.Excessive bone marrow peroxidase is relevant with some disease, comprises SLE, hashimoto struma, myasthenia gravis, rheumatic arthritis and various sclerosis.
But it is reported 2-phenyl-3-aroyl benzothiophene derivative Trombin inhibiting; Referring to EP0664126 A1.
Shown that estrogen is inhibited and the B cell had immunostimulation reaction to the T cell function.Therefore, the class estrogen compound is helpful by reply of suppressor T cell function and activating T cell relevant disease, comprise rheumatoid arthritis, multiple sclerosis disease, Guillan Barre syndrome and hashimoto struma (Holmadahl, autoimmune magazine (J.Autoimmun.) 2:651 (1989)).
Estrogen also has the additional protection effect except that inhibited to the T cell.People such as Marui (Journal of Clinical Investigation (J.Clin.Invest.) 92:1866 (1993)) report that recently antioxidant suppresses the endothelium expression of VCAM-1.VCAM-1 is the part of VLA-4, T cell and macrophage integrin, and it is relevant with the space and the Target organ that migrate out these cells from vascular system and enter around the vascular.Because estrogen is antioxidant, can expect that estrogen and analog thereof will suppress to rely on the cell transfer of VLA-4, therefore suppressed to regulate the relevant immunity series connection of disease with autoimmune.
Estrogen also plays deleterious effects in other autoimmune disease, comprises SLE and glomerulonephritis, the disease relevant with immune complex.The mechanism of the progression of disease of estrogen regulating is unknown, existing report estrogen (Flynn from the rodent body of estrin treatment, life sciences (Life Sci.), 38:2455 (1986)) have the ability to improve the phagocytosis that Fc regulates (people such as Friedman, Journal of Clinical Investigation 75:162 (1985)) and II class antigen presentation and macrophage produce IL-1.The raising of the effector functions that these macrophages are regulated might cause the immunity series connection relevant with self destruction.
EP 664123 A1 report that some 2-phenyl-3-aroyl benzothiophene is effective inhibitor of autoimmune disease.
With compare with the age male, it is littler that the women suffers from the danger of coronary heart disease before the amenorrhea; And show estrin treatment can protect amenorrhea after the women do not suffer from cardiovascular disease.Hale and Kloner have confirmed that the acute pretreat of estradiol has reduced the myocardial infarction area that male and female rabbit is caused by the coronary artery closure.U.S. Coll.Cardiol magazine 25,189 A (1995).
In male's testis and peripheral tissues, the aromatisation by testosterone can generate a spot of estrogen.Though its amount is very little, be generally 1/4th to 1/10th content less than women before the menopause, estrogen regulate male's hypothalamus hypophysis gonad, skeleton development, prostate is grown and metabolic function aspect but have important effect.In hypothalamus, testosterone causes negative feedback that gonadotropin releasing hormone and promoting sexual gland hormone are subsequently discharged to estrogenic conversion.Therefore general level and the adpedance that reduces the circulation testosterone of estrogen causes estrogenic corresponding increase.When the man was aging, the ratio of fat and lean tissue increased.The aromatisation of testosterone causes the degenerative increase of the aggregate level that increases and reduce testosterone gradually of estrogen and testosterone ratio in the fat.
Gonad hypofunction is the regular incidence of elderly men.Some studies show that, gonad hypofunction may cause with age muscle and the observable minimizing of weight of skeleton.Current research shows that but the androgen treatment can produce slight the significantly improvement of muscle strength in some gonad normal male.Testosterone lacks relevant with hip fracture, and skeleton weight is relevant with old people's testosterone concentration.
The male who accepts testosterone is being significantly improved aspect the available testosterone concentration of biology, hematocrit, right hand muscle strength and the bone calcium concentration.BUN (blood urea nitrogen)/creatinine ratio that their cholesterol levels reduces (the HDL-cholesterol does not have to change) and descends.People such as Morley, JAGS 41:149-150 (1993).
Term " prevention " is defined as the common acceptable meaning that comprises it, comprises that patient of prophylactic treatment to prevent the generation of one or more these diseases, checks the symptom of this disease constantly, and/or treats these symptoms.Therefore say suitably that the inventive method comprises two kinds of therapeutic treatment and/or prophylactic treatment.
The enforcement of method of the present invention is by giving the following formula I chemical compound of waiting to control individual effective dose.
Formula I chemical compound is useful to treatment prostatosis, thymic carcinoma, osteoporosis, endometritis, cardiovascular disease, hypercholesterolemia, and this content is recorded in the common U.S. Patent application that has 08/369,954, is hereby incorporated by.
Term " C 1-C 3Chlorine alkyl and C 1-C 3Fluoroalkyl " comprise, replace extremely methyl, ethyl, propyl group and the isopropyl of required degree from an atom to whole atoms with chlorine atom or fluorine atom.Term " C 5-C 7Cycloalkyl " comprise cyclopenta, cyclohexyl and suberyl.
Halogen refers to chlorine, bromine, iodine and fluorine.Aryl comprises arbitrarily and independently is selected from above-mentioned R 41～3 substituent group phenyl and the naphthyl that replace.DTT is a dithiothreitol, DTT.DMSO represents dimethyl sulfoxide.EDTA is an ethylenediaminetetraacetic acid.
Estrogen agonists is defined as the chemical compound that can combine with the estrogen receptor site in the mammalian tissues and can imitate estrogen action in one or more tissues herein.
Estrogen antagonist is defined as the chemical compound that can combine with the estrogen receptor site in the mammalian tissues and can stop estrogen action in one or more tissues herein.
It will be understood by those skilled in the art that some cited substituent group of the present invention may be each other or incompatible with the hetero atom in the chemical compound, and should when selecting The compounds of this invention, avoid these incompatible situations.He also should be realized that equally, and some functional group needs protecting group in synthesis step.
Those of ordinary skills should be realized that some chemical compound of the present invention can contain the atom that some have special optical or geometric configuration.The present invention comprises all these isomers; Typical laevoisomer with cis-configuration is preferred.In like manner, this technical staff it should be understood that can be by acceptable salt of the various medicines of some compound of the present invention and ester.All these esters and salt include in the present invention.
The medicine that the present invention is used for disease or disease can be prepared by common method, use conventional organic or inorganic additive, for example excipient is (as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, Pulvis Talci, calcium phosphate or calcium carbonate), binding agent is (as cellulose, methylcellulose, hydroxy-methyl cellulose, polypropylpyrrolidone, polyvinyl pyrrolidone, gelatin, arabic gum, Polyethylene Glycol, sucrose or starch), distintegrant is (as starch, carboxymethyl cellulose, hydroxypropyl starch, the hydroxypropyl cellulose of rudimentary replacement, sodium bicarbonate, calcium phosphate or calcium citrate), lubricant is (as magnesium stearate, light anhydrous silicic acid, Pulvis Talci or sodium lauryl sulfate), correctives is (as citric acid, methanol, glycine or Fructus Citri tangerinae powder), antiseptic is (as sodium benzoate, sodium sulfite, methyl parahydroxybenzoate or propyl p-hydroxybenzoate), stabilizing agent is (as citric acid, sodium citrate or acetic acid), suspending agent is (as methylcellulose, polyvinyl pyrrolidone or aluminium stearate), dispersant (as hydroxypropyl emthylcellulose), diluent (as water) and substrate wax (as cupu oil, white vaseline or Polyethylene Glycol).In medical composition, active component can be the amount that reaches required therapeutic effect, and for example, oral and single agent content parenterai administration is 0.1～50 milligram.
The every single agent of active component contains the 0.1-50 milligram, and every day, still above-mentioned dosage can suitably change to some extent according to patient age, body weight, the state of an illness and administering mode to patient's administration one to four time usually.Preferred dose is the 0.25-25 milligram.Preferred every day potion.
By following flow chart, chemical compound of the present invention can prepare at an easy rate.
The chemical compound of some formula I can be easily in the solvent of reactionlessness with a kind of noble metal catalyst hydrogenation of formula (II):
Unsaturated intermediate and make; Pressure and temperature is not very crucial, and hydrogenation is generally at 20～80 pounds/inch 2Carried out several hours and finish in room temperature under the hydrogen-pressure.
As needs, hydrogenated products separates, purification, and uses acidic catalyst to decompose ether in reaction-inert solvent, and its temperature is about 0 ℃～100 ℃ according to used acidic catalyst.Find HBr, 0 ℃ of BBr under the high temperature to ambient temperature 3And AlCl 3To this reaction effectively.
Product, formula I chemical compound is with standard method separation and purification.
Wherein A is CH 2, and B, D and E are that the formula II intermediate of CH is recorded in United States Patent (USP) 3,274,213; Pharmaceutical chemistry magazine (J.Med.Chem.) 10,78 (1967); Pharmaceutical chemistry magazine 10,138 (1967); With pharmaceutical chemistry magazine 12,881 (1969), be incorporated herein its disclosure as a reference.They also can be by following method preparation.
The preparation of flow process 1 expression I chemical compound, e=1 wherein, A=CH 2, Z 1=OCH 2CH 2, G=Cycloalkyl amine, B=CH.Under elevated temperature, in polar non-solute such as dimethyl formamide, adopt potassium carbonate as alkali, with corresponding N-chlorethamin the 4-bromophenol is carried out alkylation, make chemical compound 1-2, D wherein and E are CH.Preferred temperature is 100 ℃.D or E or both are chemical compound 1-2 synthetic of N, are under condition of phase transition, and the ethoxy Cycloalkyl amine is gone up at two bromo chemical compounds (1-1) and nucleophilic substitution takes place generated bromo-amine (1-2) and finish.Synthetic (Synthesis), 77,573 (1980).Then with just-butyl lithium or magnesium metal carry out after metal halide exchanges, bromo-amine (1-2) has generated corresponding lithium or reactive magnesium thing, this reactant at low temperatures, in the presence of strontium chloride, preferred (no strontium chloride reaction is carried out as usual) and 6-methoxyl group-1-1,2,3,4-Tetrahydrooxonaphthalene reaction generate methanol (derivant) (1-3) or acid effect back be styrene (1-4).For example pyridinium bromide bromide processing methanol (1-3) or styrene (1-4) obtain bromostyrene (1-5) excessively with bromating agent.Aryl or heteroaryl zinc chloride or aryl or heteroaryl bromic acid and the reaction of (1-5) bromide are reflected at palladium metal catalyst and for example carry out under the existence of tetrakis triphenylphosphine palladium (0), have generated diaryl styrene (1-6).[theoretical and applied chemistry (Pure ﹠amp; Applied Chem.63,419, (1991) and Bull.Chem.Soc.Jpn. (Japanization association bulletin) 61,3008-3010, (1988)].Be the preparation preferred compound, use the phenyl zinc chloride of replacement or the phenyl bromic acid of replacement in the reaction.The preparation of aryl zinc chloride is by corresponding lithium reactant and anhydrous zinc chloride quenching and get.The aryl bromic acid can not obtain on market, can be handled by corresponding aryl lithium reactant and trialkyl bromate (being preferably trimethyl or triisopropyl bromate) quenching, and the acid effect is handled and prepared then.Acta?Chemica?Scan，47，221-230(1993)。The lithium reactant that can not buy can be by corresponding bromide or halogenide and just-and butyl or tert-butyl lithium carry out halogen metal exchange system and get.In addition, the lithium reactant also can assist lithiation (lithiations) to prepare by hetero atom, is recorded in " organic reaction (Organic Reactions) ", and 27 volumes are in the chapter 1.In the presence of the palladium dydroxide on the active carbon for example, 1-6 is carried out catalytic hydrogenation obtain corresponding dihydro methoxyl group intermediate, then carry out demethylation, obtain the chemical compound of (1-7) with the hydrogen bromide solution in 45% acetic acid of the Boron tribromide in 0 ℃ the dichloromethane or 80-100 ℃.These chemical compounds are racemic, and by the pillar of high pressure liquid chromatography with chiral stationary phase, for example, Chiralcel OD post can be split as enantiomer with it.In addition, optically pure salt, as 1,1 '-diastereoisomeric salt that the basic hydrophosphate of dinaphthyl-2,2 '-two forms, recrystallization is finished optical resolution.
(1-7) cis-structure of chemical compound can become transconfiguration with alkali treatment.
When D and/or E are nitrogen, intermediate (formula II) and formula I chemical compound can be prepared by corresponding dihalo-pyridine or pyrimidine shown in flow process 1, and embodiment 6 has described preparation 6-phenyl-5-[6-(2-pyrrolidine-1-base-ethyoxyl) pyridin-3-yl in detail]-5,6,7,8-naphthane-2-alcohol.
E=1 wherein, A=CH 2, Z '=OCH 2CH 2, the G=pyrrolidinyl, D, E, B=CH, the methyl ether of the formula I chemical compound of Y=Ph can be prepared as follows easily: in the inert reaction solvent in the presence of the noble metal catalyst, the first step is to NSC-70735 (Upjohn ﹠amp; Co., 700 Portage Road, Kalamazoo, Michigan 49001) carry out hydrogenation.The requirement of pressure and temperature is not tight, room temperature and 50 pounds/inch in ethanol 2Pressure under, the reaction carried out at an easy rate about 20 hours.
Second step was that methoxyl group is decomposed, this can be at room temperature with the Boron tribromide or finish at an easy rate with the hydrogen bromide in the acetic acid for example of the acidic catalyst in the reaction-inert solvent at 80-100 ℃ time.Product separates with conventional method, and is converted into ackd salt if needed.
B is the method preparation of the formula I chemical compound of nitrogen by flow process 2 and 3, is recorded in embodiment 3-5 and 10-12.
The preparation of the formula I chemical compound of B=N is shown in flow process 2.Aryl acyl chlorides (2-1) is handled with primary amine, obtains aryl secondary amide (2-2), is secondary amine (2-3) with the lithium aluminium hydride reduction in the ether solvent then.Then carrying out acidylate with aroyl chloride gets tertiary amine (2-4), at the phosphorus oxychloride cyclisation generation dihydro-isoquinoline salt (2-5) of heat.Sodium borohydride reduction generates the alcoxyl tetrahydroisoquinoline, obtains target compound with the Boron tribromide demethyl in the dichloromethane then.
Wherein synthesizing in flow process 3 of the formula I chemical compound of B=N also is described.Secondary amine (3-1) obtains tertiary amine (3-3) with benzyloxy aroyl chloride (3-2) acidylate, with the phosphorus oxychloride cyclisation generation dihydro-isoquinoline salt (3-4) of heat.Behind sodium borohydride reduction (3-4), then obtain isoquinolin (3-5) with the aqueous hydrochloric acid solution debenzylation, the functionalized chloride alkylation that its reuse is fit to, and with Boron tribromide demethyl acquisition target compound.Flow process 2
Figure A9710341500291
In each flow chart, the implication of following symbol is as follows: Ar: aryl Ph: phenyl PYRHBrBr 2: cross the bromination pyridinium bromide.
Flow process 1
Figure A9710341500301
Flow process 3
Though the free alkali form of formula I chemical compound can be used for the inventive method, the form of preferred for preparation and a kind of drug acceptable salt of use.Therefore, the addition salts of the acceptable bronsted lowry acids and bases bronsted lowry of compound formation medicine that uses in the inventive method, acid is various mineral acids, preferred organic acid, and comprise physiological acceptable salt commonly used in the pharmaceutical chemistry.These salt also are parts of the present invention.The mineral acid that is used to form this salt comprises: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, hypophosphoric acid etc.Also can use by the organic acid derived compounds, for example, aliphatic monobasic or dicarboxylic acids, the alkanoic acid that phenyl replaces, hydroxyl alkane alkyd and hydroxyl alkanol binary acid, aromatic acid, the sulfonic acid of aliphatic series and aromatics.Therefore these drug acceptable salts comprise: acetate, phenylacetate, trifluoroacetate, the allyl hydrochlorate, Ascorbate, benzoate, chloro benzoate, dinitro-benzoate, the oxybenzene formates, methoxybenzoic acid salt, ar-Toluic acid salt, o-acetyl-p-methoxybenzoic acid salt, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyric acid salt, beta-hydroxybutyric acid, butine-1,4-glycol hydrochlorate, hexin-1,4-glycol hydrochlorate, caproate, caprylate, chloride, cinnamate, citrate, formates, fumarate, glycollate, enanthate, hippurate, lactate, benzene fruit acid salt, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinate, .gamma.-pyridinecarboxylic acid salt, nitrate, oxalates, phthalate, terephthalate, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionic acid salt, Salicylate, sebacate, succinate, suberate, sulfate, disulfate, pyrosulfate, sulphite, bisulfites, sulfonate, benzene sulfonate, right-bromobenzenesulfonate, chlorobenzene sulfonate, esilate, the 2-isethionate, mesylate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, right-toluene fulfonate, xylenesulfonate, tartrate etc.Preferred salt is citrate.
The acceptable acid-addition salts of medicine generally is through type I chemical compound and waits mole or excessive acid reaction preparation.Reactant is usually in for example combination in ether or the benzene of mutual solvent.This salt generally is precipitated out from solution in one hour to 10 days, and can isolated by filtration or remove with conventional method and to desolvate.
Compare with its parent compound, the drug acceptable salt of formula I chemical compound generally has solubility property preferably, therefore is easy to make the preparation of liquid or emulsion form.
In case preparation is finished, the free alkali of formula I chemical compound or salt form can be taked method described herein to deliver medicine to and treat the smelting individuality.Following non-limiting experimental example illustrates method of the present invention.
In the methods of the invention, formula I chemical compound successive administration or administration in a day are 1 to 4 time.
Term herein " effective dose " refers to suppress the chemical compound amount of the inventive method of pathological symptom performance herein.According to the present invention, the concrete dosage of the administration of chemical compound should be determined according to specific case situation, for example, gives drug compound, administering mode, patient condition and the order of severity of the reason symptom of waiting to cure the disease.Common daily dose comprises nontoxic dosage level, is the about 0.25mg of a kind of chemical compound of the present invention～about 100mg/ days.Preferred daily dose is about 10mg～about 40mg/ days.
The compounds of this invention can be via various administrations, comprise oral, rectum, transdermal, subcutaneous, intravenous, intramuscular and nasal cavity.These chemical compounds preferably form preparation before administration, how to select to be determined by the clinicist.Usually, formula I chemical compound or its drug acceptable salt combine with a kind of medicine acceptable carrier, diluent or excipient to form pharmaceutical preparation.
Total active ingredient accounts for 0.1% to 99.9% of preparation total amount in such preparation." medicine can be accepted " refer to carrier, diluent, excipient and/or salt must with other composition compatibility of preparation, and harmless to patient.
Adopt the known technology method of this area and the composition of known easy acquisition, can prepare the pharmaceutical preparation that contains formula I chemical compound.For example, tablet, capsule, suspending agent, powder or the like be prepared and be made to formula I chemical compound can with general excipient, diluent or carrier.The example that is suitable for carrier, excipient and the diluent of this preparation comprises following filler and bulking agent, for example starch, sucrose, mannitol and silica derivative binding agent (as carboxymethyl cellulose and other cellulose derivative), alginate, gel and polyvinylpyrrolidone; Wetting agent is glycerol for example; Distintegrant is calcium carbonate and sodium bicarbonate for example, postpones lytic agent such as paraffin; Absorption enhancer such as quaternary ammonium compound; Surfactant such as spermol and glyceryl monostearate, absorption carrier be Kaolin and Bentonite for example; Lubricant is Pulvis Talci, calcium stearate and magnesium for example, and solid polyethylene glycol.
This chemical compound can be made elixir or pharmaceutical solutions for conveniently oral, or makes the solution that is suitable for parenterai administration, for example is used for intramuscular, subcutaneous or intravenous administration.
In addition, this chemical compound is suitable for making slow releasing preparation etc. very much.This preparation so forms that make it can a release of active ingredients or preferably may discharge in a certain specific physiological location in one section duration.Covering, container and protection substrate can be made by for example polymer or wax.
Formula I chemical compound is generally to make things convenient for the preparation administration.Following example of formulations only is used for explanation but not is intended to limit the scope of the invention.
In following preparation, " active ingredient " refers to a kind of compound or its salt of formula I.
Preparation 1: gelatine capsule
Hard gelatin capsule is prepared as follows:
Become deal (mg/ capsule)
Active ingredient 0.25-100
Starch, NF (National Formulary) 0-650
The starch powder 0-50 that can flow
Siloxanes fluids, 350 centistoke 0-15
Use a kind of tablet formulation of these composition preparations as follows:
Preparation 2: tablet
Become deal (mg/ sheet)
Active ingredient 0.25-100
Cellulose, crystallite 200-650
Silicon dioxide, foamed 10-650
Stearic acid 5-15
These components are mixed and be pressed into tablet.
In addition, every preparation tablets that contains the 0.25-100mg active ingredient is as follows:
Preparation 3: tablet
Become deal (mg/ tablet)
Active ingredient 0.25-100
Starch 45
Cellulose, crystallite 35
Polyvinylpyrrolidone 4
(10% aqueous solution)
Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5
Pulvis Talci 1
Active ingredient, starch and cellulose filter numbering 45 order U.S. sieves (No.45 mesh U.S.sieve) and thoroughly mix.Polyvinylpyrrolidone and gained powder mixes filter numbering 14 order U.S. sieves then.So the granule of gained is at 50-60 ℃ of drying and filtration numbering 18 order U.S. sieves.Sodium carboxymethyl cellulose, magnesium stearate and Pulvis Talci filter numbering 60 order U.S. sieves, add then in the granule, mix the back and be pressed into tablet on tablet machine.
The unit suspending agent that per 5 milliliters of medicaments contain the 0.25-100mg active ingredient is prepared as follows:
Preparation 4: suspending agent
Become deal (mg/5ml)
Active ingredient 0.25-100mg
Sodium carboxymethyl cellulose 50mg
Syrup 1.25mg
Benzoic acid solution 0.10ml
The flavoring agent capacity
The coloring agent capacity
Purified water is to 5ml
Medicament filters numbering 45 order U.S. sieves, and mixes the sliding property pastel of formation with sodium carboxymethyl cellulose and syrup.The benzoic acid, flavoring agent and the coloring agent that under agitation add dilute with water.The water that adds capacity then is to volume required.Preparation contains the aerosol of following composition:
Preparation 5: aerosol
Become deal (% weight)
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chloro difluoromethane) 70
Active ingredient mixes with ethanol, and mixture is added in a part of propellant 22, is cooled to 30 ℃, and moves to a filling device.Dilute with rustless steel container of aequum adding and with residual propellant then.The container of then valve member being packed into.
Suppository is prepared as follows:
Preparation 6: suppository
Become deal (mg/ bolt)
Active ingredient 250
Saturated fatty acid glyceride 2000
Active ingredient filters numbering 60 order U.S. sieves, and is suspended in the saturated fatty acid glyceride that uses minimum necessary heat fusing in advance.Then one of mixture impouring is generally in the bolt mould of 2 gram volumes and cools off.
The formulation preparation that intravenous is used is as follows:
Preparation 7: intravenous solution
Become deal
Active ingredient 20mg
Isotonic saline solution 1,000ml
The solution of said components injects in the patient body with about one minute one milliliter of speed intravenous.
Suppress the detection of Alzheimer disease
EP 0659418 A1 has put down in writing the detection to treatment AD compounds effective.
Amylopectin can be purchased (the Torrance in Bachem Inc., the California), peninsula laboratory company (Peninsula Laboratories, Inc. (Belmont, and sigma chemistry product company (Sigma Chemicals (St.Louis, the Missouri State)) California)).Amyloid-β (1-40) and anti-beta amyloid peptide (40-1) can be purchased in Bachem.Inc..β 2-microglobulin can be purchased in Sigma Chemicals (St.Louis, the Missouri State).
Peptide stock solution (1mM) is diluted to indication concentration in prepared fresh and the culture medium that requiring in the aseptic water of no thermal source.Handled Mus Hippocampus culture (external 10-14 days) four days with peptide or excipient.The survival of Corium Mus matter culture is observed with the microtechnique that compares and is judged and come quantitatively with the lactic acid dehydrogenase (LDH) that measurement is discharged into culture medium.
Detect 1
Adopt former Mus hippocampal neuron of standard cell lines culture technique In vitro culture.Amyloid-β (A β) peptide adds in the cultured cells with the normal toxicity concentration of 25 μ m.Handle after 4 days, viability is estimated by the LDH that measurement is released in the culture medium.Detect (Sigma catalog number (Cat.No.) #228-20) with 96 orifice plates at the dynamic (dynamical) LDH of standard 340nm and in the DMEM aliquot that the condition of 20 μ l volumes is determined, measure LDH.Analysis is carried out on PC-driving EL 340 little dish biodynamics (MicroplateBiokinetics) dish readout instruments (Bio-Tek instrument) at 37 ℃, and data analysis Delta Soft II software (the 3.30B version, BioMetallics, Inc.).Each detect the Serum LDH level all contain standard and rising (as, Sigma enzyme matched group 2N and 2E) the quality reference standard.The result is upgraded to unit representation with LDH/, and wherein 1 unit definition is under testing conditions, and per minute catalysis generates the amount of the required enzyme of 1 micromolar nadide.To protection research, before handling with A β and/or simultaneously, a kind of chemical compound of formula I joins in the culture.
The minimizing of the active available LDH that is released into culture medium (neurotoxicity indicator) with respect to matched group of formula I chemical compound illustrates.
Detect 2
5～15 Mus are carried out 15 minutes four vessel sealings so that general ischemia.Before the closed back 15 minute hour, simultaneously and/or give laboratory animal and control animal chemical compound of the present invention after several hours.The ischemic infringement was put to death animal after 3 days, and observed assessment Hippocampus and striatal neuronal damage with the normal structure method.
The activity of formula I chemical compound illustrates with the minimizing of neuronal damage.
Detect 3
Select 5～15 women to carry out clinical research.After the women is amenorrhea, promptly before the research beginning, stopped menstruation 6～12 months, they suffer from early stage AD at diagnosis, and expect that the AD symptom will worsen during studying, but the others health status is good.Research has the placebo group, and promptly the women is divided into two groups, and a winding is subjected to chemical compound of the present invention, and another winding is subjected to placebo.The memory relevant with AD, discernment, extrapolability and other symptom to patient are carried out the datum mark labelling.Experimental group women's every day oral 10～100mg active substance.Their continued treatment 6～36 months.The symptom of making the datum mark labelling to two groups is all made accurate record, and when research finishes these results is compared.Before the research beginning, the result not only compares between every group member, and each patient's result also compares with the symptom of each patient report.The activity of tested medicine is illustrated by typical discernment decline and/or the weakening of behavioral disorder relevant with AD.
More than at least one the activity of Jian Ceing can prove the practicality of formula I chemical compound.
The PMS/LLPDD method of testing
Select 3～15 women to carry out clinical research.Women's eumenorrhea, in good health, suffer from one or more above-mentioned PMS/LLPDD symptoms.Because these symptoms have the feature of idiosyncrasy and self awareness, research also has the placebo group, that is, the women is divided into two groups, and a winding is subjected to activating agent of the present invention, and another winding is subjected to placebo.Experimental group women's every day oral 10～100mg medicine.Their continued treatment 1～3 month.The equal accurate recording of the number of two groups symptom and degree, and when research finishes, these results are compared.Before the research beginning, the result not only compares between every group member, and each patient's result also makes comparisons with each patient's report symptom.Referring to United States Patent (USP) 5,389,670.
By using the positive influence of as above studying one or more symptoms, the practicality that chemical compound of the present invention suppresses the PMS/LLPDD symptom can obtain explanation.
Suppress the experimental technique experiment 1 of amenorrhea front and back syndrome
Select one group of 3～20 women of 40～50 years old as experimental group.The womankind all shows at least a disease that amenorrhea brought that is about to.The compounds of this invention was with 10-100mg/ days dosed administration and pay close attention to the symptom development.3 weeks of administration The compounds of this invention.Experiment 2
Carry out and experiment 1 identical experiment, but treating administration time is 3 months.Experiment 3
Carry out and experiment 1 identical experiment, except administration time is 6 months.
Be defined as in this " activity ", the stopping fully or alleviate or do not take place of one or more symptoms of patient, or enter state after the amenorrhea fast, above-mentioned each detect and show that all The compounds of this invention is effective to syndrome before and after the treatment amenorrhea.
The detection of the thrombemodulin expression that increases
Below detection is recorded among EP 0659427 and the US 5476862, is hereby incorporated by.
Detect 1
For further effect, intimal smooth muscle cells and its effect in improving the blood anticoagulant knot of understanding formula I chemical compound, be necessary that research is in the active variation of these cell surface thrombomodulins (TM).Formula I chemical compound also can be used to reverse/proofread and correct the effect of the active instrumentality that reduces of those TM that make at cell surface.
About 40,000-80,000 early stage endothelium that inserts (tremulous pulse, venous or little subcutaneous), or the smooth muscle cell of inner membrance is seeded in and grows into fusion on 24 porocyte culture plates.With Hank buffer salt solution (HBSS) or serum-free medium (SFM) order washed cell monolayer 2～3 times.In 24 hours, the formula I chemical compound of various concentration (scope from the micromole to pmol) adds cell in triplicate.Cell in negative control hole remains in the serum-free medium, and all give the excipient of equivalent in porose.
Measuring the active existing method of cell surface TM is to use two step amide to decompose detection.In the first step that detects, after HBSS or the SFM washing, contain α-thrombin (final concentration 0.1 NIHU/ml) adding monolayer of the 0.4ml SFM (final concentration 11.2 μ g/ml) of human protein C and people and at 37 ℃ and 5%CO 2Middle incubation.At 15,30 and 45 minutes time points, from each hole, move the culture medium of 100 μ m and in micropore, add to about 5 minutes of the excessive hirudin of 50 μ l under 37 ℃ so that further anticoagulant enzymatic activity.As mentioned above, do not exist under the cell, the mixture of SFM and protein C and α-thrombin uses and carries out the similarity reason as negative control.
In second step of detecting, the substrate 3mM 2366 about 50 μ l that add lustre to of protein C add in the culture/hirudin mixture that regulates, and the automatic plate readout instrument measurement of OD 405 employings, to monitor the kinetics mechanism of TM activity in 4 minutes.This dynamic analysis one is finished, and uses the BCA method to measure gross protein.Final TM activity is represented to increase %.
Detect 2
The septicemia baboon model that the described E-Coil bacterium of US 5009889 (being hereby incorporated by) causes is used to confirm that formula I chemical compound is as the effectiveness of antithrombotic agents and the ability of their adjustment inflammation initiation endothelial function disturbances.
The practicality of The compounds of this invention can be confirmed by the following result shown in above-mentioned arbitrary detection: to the positive influence of expression, coagulant imbalance or the protein C activation rate feature of thrombomodulin.
Experiment to the fibrosis of uterus inhibition
Experiment 1
3～20 women that suffer from fibrosis of uterus give chemical compound of the present invention.This chemical compound dosage is 0.1～100mg/ days, 3 months administration phases.
Observe these women in three months after medication period and drug withdrawal, to observe to the Fibrotic influence in uterus.
Experiment 2
With experiment 1, but medication period is 6 months.
Experiment 3
With experiment 1, but medication period is 1 year.
Experiment 4
A. in guinea pig, bring out fibroadenoma
On one's body sexually matured female guinea pig, stimulate to bring out leiomyoma with estrogen for a long time.To animal injection estradiol, inject about 2～4 months or weekly 3～5 times until generating tumor.Treatment comprises and gives chemical compound of the present invention or about 3～16 weeks of excipient, puts to death animal then and extracts the uterus and analyze tumour regression.
B. human uterus's fibrous tissue is transplanted to nude mice
Transplant in the peritoneal cavity of female nude mice of sexually matured, castrating and/or myometrium from the mankind's leiomyoma.The estrogen that injects external source is to bring out the growth of transplanted tissue.In some example, the tumor cell of collection is cultivated outside transplanting precursor.Treatment comprises that gastric lavage treats chemical compound of the present invention or 3～16 weeks of excipient every day, and takes out graft and measure its growth or degeneration.During execution, collect the uterus to estimate the situation of organ.
Detect 5
A. gathered from the mankind's fibrosis of uterus tumor, and remained on external as main non-distortion culture.Surgical samples by aseptic net or sieve or from surrounding tissue, pick from preparation single-cell suspension liquid.In the culture medium that contains 10% serum and biocide, keep cell.Measure and have or do not exist estrogenic rate of growth.Pair cell is analyzed the ability and they reactions to somatomedin and growth hormone that they generate supplemental components C3.External their reproductions after treating with progesterone, GnRH, a kind of chemical compound of the present invention and excipient of culture analysis are reacted.The content of analyzing the sterols hormone receptor weekly is to determine whether important cell characteristic keeps external.Adopt 5-25 name patient's tissue.
At least a above analytical activity confirms that chemical compound of the present invention is competent in the treatment fibrosis of uterus.
The detection that confirmation suppresses myeloperoxidase (MPer)
Detect 1
For research formula I chemical compound is suppressing the active feature of myeloperoxidase (MPer), the detection 1 and 2 of adopting Jansson (Supra.) to describe.
In this detection, in the presence of additional hydrogen peroxide, the PMN platelet of using the estriol stimulating human is to increase the activity of myeloperoxidase (MPer).The chemoluminescence method measurement conversion of chloric acid to luminol.Reactant mixture contains cell (10 6), reagent or formula I chemical compound (1 μ m), hydrogen peroxide (0.1mM), and luminol (0.2mM) is at 37 ℃ of following incubations.
Estrogen and its analog stimulate the myeloperoxidase (MPer) activity.The chomiluminosity that formula I chemical compound antagonism estriol excites.
Detect 2
In the presence of 37 ℃ of luminols, with the human myeloperoxidase (MPer) of purification with estrogen or formula I chemical compound incubation.The substrate hydrogen peroxide adds and the measurement chemiluminescence.Reactant mixture is human MPE (250ng), reagent or formula I chemical compound (10 μ m, titration), hydrogen peroxide (1mm) and luminol (0.2mm).
Estrogen and analog thereof do not have the MPE activity or are seldom influential, but formula I chemical compound reduces the activity of the MPE of purification.
Detect 3
Select 5～15 women to carry out clinical research.The womankind suffers from SLE or rheumatoid arthritis.Because idiosyncrasy that these are sick and self awareness feature, research has the placebo group, that is, the women is divided into two groups, and wherein a winding is subjected to formula I chemical compound as active substance, and another winding is subjected to placebo.Experimental group women every day oral 50～100mg medicine.Treatment continues 3～12 months.Symptom quantity and degree to two groups are held accurate recording, latter stage these results are compared in research.The not only result between two group memberships relatively, and each patient's result also with begin one's study before each patient report symptom relatively.
The practicality of formula I chemical compound can be influenced by the positive of above-mentioned at least one detection and illustrates.
The detection of Trombin inhibiting is described
Method-t-P ADissolved influence to the human plasma caking
The following formation in little test tube of human plasma caking: (73NIH unit/ml) contains 0.0229 μ Ci's in the serum to 100 μ l human serums to add 50 μ l thrombins 125The Fibrinogen of I labelling.By (50,100 or 1000 units/ml) are coated in and study the caking dissolving on the caking, and room temperature incubation 20 hours with 50 μ l urokinases or streptokinase.Behind the incubation, centrifuge tube in Beckman Microfuge.25ml supernatant liquid layer is added 0.03m tris (trometamol)/0.15M NaCl buffer of 1.0ml so that carry out γ-counting.Save thrombin (with alternative buffer) and obtain counting matched group 100% dissolving.Estimate may influencing each other of thrombin inhibitor and fibrinolysis by chemical compound being added upper solution (concentration 1,5 and 10 μ g/ml).Concerning the specific concentrations of fibrinogenolysis, roughly estimate IC from the 50% dissolved value that some data points are extrapolated to representative by linear extrapolation 50Value.
The anti-agglomeration activity
Material
From clear-headed hybrid hunting dog (male or female, Hazelton-LRE Kalamazoo, the Michigan, the U.S.) or from anaesthetizing male Sprague-Dawley Mus (Harlan Sprague-Dawley, Inc., Indianapolis, the state of Indiana, the U.S.) annotate 3.8% citrate with intravenous injection and obtain dog plasma and Mus blood plasma.From instant ACD (ACD) human blood, prepare Fibrinogen as part 1-2 according to previous method and explanation.Smith, biochemical magazine, 185,1-11 (1980); With people such as Smith, biochemistry (Biochem.J.), 11,2958-2967 (1972).The human fibrinogen of 98% pure/no blood plasma enzyme purchases in Connecticut, USA, Greenwich, U.S. diagnosis product company (American Diagnostica, Greenwich).Coagulating agent ACTIN Thromboplastin and human plasma are from Fla. Baxter Healthcare Corp, Dade Division, Miami, Florida State.Making coagulation detection from the thrombin of the cattle of Parke-Davis (Ann Detroit, Michigan) in blood plasma uses.
Method
Anti-agglomeration mensuration
The coagulation assay method as previously mentioned, people such as Smith, thrombosis research (ThrombosisResearch), 50,163-174 (1988).(American LABor Inc.) is used to carry out all coagulation detection to a kind of CoAScreener coagulation instrument.Measure the thromboplastin time (PT) by adding 0.05ml saline and 0.05ml thromboplastin-C reagent to 0.05ml test blood plasma.Add 0.05ml CaCl after 120 seconds by 0.05ml experiment blood plasma and 0.05ml Actin reagent incubation 2(0.02M) measure thromboplastin time (APTT) of activated partial.Measure thrombin time (TT) by adding 0.05ml saline and 0.05ml thrombin (10NIH units per ml) to 0.05ml test blood plasma.Formula I chemical compound adds in human or animal's blood plasma of extensive concentration the prolongation influence that APTT, PT and TT is detected to determine.Estimate to double the concentration of the setting time of each detection with linear extrapolation.
Animal
Male Sprague Dawley Mus (350～425gm, Harlan Sprague Dawley, Inc.Frdianapolis, the state of Indiana) usefulness xylazine (20mg/kg, subcutaneous) and ketamine (120mg/kg, subcutaneous) anaesthetize and place one to add (37 ℃) on the hot water blanket.Sleeve pipe inserts in jugular vein so that inject.
Artery-vein bypass model
Left side jugular vein and right carotid are inserted into 20 centimeter length polythene PEs, 60 pipes.The 6cm that has cotton thread (5cm) at intracavity is loaded between the long district to finish the arterial-venous bypass circuit than the center friction of bassoon (PE 190).Blood circulated in bypass 15 minutes, and cotton thread carefully takes out and weighs then.From cotton thread and thrombosis gross weight, deduct the weight (referring to J.R.Smith, Britain pharmacology magazine (Br.J.Pharmacol.), 77:29,1982) of wet cotton thread.
The FeCl of arterial injury 3Model
By center line veutro neck cutting and separating carotid artery.Below each tremulous pulse, place thermocouple and continuous record blood vessel temperature on the bar diagram instrument.A pipe box (0.058 ID * 0.077 OD * 4mm, Baxter medical grade siloxanes (Baxter Med.Grade Silicone)) vertically cuts, and places around each carotid artery that is located immediately on the thermocouple.FeCl 36H 2O is soluble in water, and its concentration (20%) is with FeCl 3Actual concentration represent.Be damage tremulous pulse and the generation of initiation thrombosis, draw 2.85 μ l with dropper and move in the pipe with the tremulous pulse on the washing thermocouple probe.Temperature reduces rapidly and has shown arterial occlusion.Closing time is with a minute expression, and FeCl is used in representative 3And the blood vessel temperature reduce rapidly between institute's elapsed time (referring to K.D.Kurz, thrombosis research (Thromb.Res.), 60:269,1990).
Spontaneous thrombosis generation model
Vitro data shows, peptide thrombin inhibitor Trombin inhibiting and other serine protease, for example, blood plasma enzyme and plasminogen activator.Suppress fibrinolysis for whether assessing in the chemical combination object, measure spontaneous thrombosis formation speed by the whole blood caking of labelling is implanted pulmonary circulation.Mus blood (1ml) and little thrombin of beef (4IU, Parke Davis) and 125(5 μ Ci, ICN) rapid mixing are injected elastic tube and 37 ℃ of incubations 1 hour to the I Fibrinogen immediately.The ageing thrombosis is shifted out in the pipe, be cut into the 1cm fragment, washing is 3 times in common saline, and each fragment is counted on the γ calculating instrument.A fragment of known counting is pumped into conduit, implants jugular vein subsequently.Catheter tip enters near the right atrium and discharges caking so that drift about in pulmonary circulation.Transplant after 1 hour, collect cardiopulmonary and also count respectively.Thromboembolism is with hundred
Figure A9710341500421
The fibrinolysis of implanting caking is the function of time.(referring to, J.P.Clozel, cardiovascular pharmacology, 12:520,1988).
Coagulation parameter
Thrombin time of blood plasma (TT) and activatory partial prothrombinase time (APTT) measure with fiber instrument (fibrometer).Blood is sampled from the neck conduit and is collected in the syringe that contains sodium citrate (3.8%, 1 part to 9 parts of blood).Be to measure TT, Mus blood plasma (0.1ml) and saline (0.1ml) and thrombin of beef (0.1ml, 30U/ml in the Tris buffer, Parke Davis) are 37 ℃ of mixing.As for APTT, blood plasma (0.1ml) and APTT solution (0.2 μ l, Organon Teknika) were cultivated 5 minutes at 37 ℃, added CaCl 2(0.025M) to begin caking.Repeat twice detection and average.
But biology availability index
The increase of supposing TT just since the thrombin of parent compound suppress to cause, so bioactive measurement, the measurement of TT is as the substitute of detection parent compound.Roll into a ball in the anesthesia Mus and behind the clear-headed Mus of oral medication fasting at the intravenous injection medicine, determine the time period of thrombin inhibitor the TT influence.Because two groups of Mus are used in the restriction of blood volume and need decision from the restriction of counting of time period of value before return treatment when reaction treatment time.Each experiment member represents the sequential time point of alternate, uses the average T T of whole time period to come area (AUC) under the calculated curve.The biological activity index is as shown in the formula calculating and be expressed as relative activity percent.The area under curve of blood plasma TT time period (AUC) is measured and adjust according to dosage.But this biology availability parameter is expressed and is calculated as follows with " % relative activity ":
Chemical compound
In common saline every day prepared fresh compound solution and inject as medicine group injection or in preceding 15 minutes of perturbation of experiment or whole process.Medicine group's volume injected is intravenous 1ml/kg, oral 5ml/kg, and the injection volume is 3ml/hr.
Statistics
The result is expressed as on average+/-SEM.Measuring statistical significant difference with unidirectional differential analysis, is different with which meansigma methods of Dunnett ' s experiment decision then.The significant level of casting out the invalid prerequisite of same average value is P＜0.05.
Animal
Dog (Beagles, 18 months-2 years; 12-13kg, Morshall Farms, North Rose, New York 14516) overnight fasting and after medication, feed the prescription food (Purina Mills, St.Louis, the Missouri State) 240 minutes of Purira approval.Drink water arbitrarily.Room temperature keeps 66-74 °F; The 45-50% relative humidity; Illumination 06:00 to 18:00.
Pharmacokinetics model
Before taking medicine, make the 5mg/ml goods and prepare experimental compound by being dissolved in aseptic 0.9% saline.The oral experimental compound single dose of Canis familiaris L. 2mg/kg.0.25,0.5,0.75,1,2,3,4 and 6 hours vein blood samplings (4.5ml) from the head after the medication.Sample collection and remains on ice before falling heavy blood plasma centrifugal in the Vacutainer of Citrated test tube.Plasma sample is analyzed with dinitrophenyl hydrazine derivatization and with HPLC (Zorbax SB-C8 post), and eluent is for transferring to methanol/500mM sodium acetate of pH7 with phosphoric acid (60: 40, volume/volume).Write down the plasma concentration of experimental compound, and calculate pharmacokinetic parameter: release rate constant, Ke with it; Total clearance, Clt; Volume of distribution, V DThe time of experimental compound maximal plasma concentration, Tmax; Chemical compound when Cmax or Tmax, Cmax; The blood plasma half-life, t 0.5And area under curve, A.U.C; The mark that experimental compound absorbs, F.
The dog model that crown animal thrombosis generates
People such as Jackson are prepared and operate in the operation of Canis familiaris L., circulation (Circulation), and 82, on the books among the 930-940 (1990).With pentobarbital sodium (30mg/kg, intravenous injection) anesthesia hybrid hunting dog (6-7 monthly age, male or female, Hazelton-LRE, Kalamazoo, Michigan, the U.S.), insert conduit and feed room air.Variation volume and respiratory frequency are adjusted to and keep blood PO 2, PCO 2With pH in normal range.Insert subcutaneous probe electrode to write down plumbous II ECG.
The side neck separates left jugular vein and common carotid artery in the incision left side.The Millar perforator of pre-calibration (MPC-500 type, Millar instrument company, Houston, TX, the U.S.) inserts carotid artery vascular, continuous monitoring arteriotony (ABP).In experiment, cannulate in jugular vein so that blood sampling.In addition, the femoral vein of two back legs is inserted into sleeve pipe to give experimental compound.
Carry out left thoracotomy at the 5th Intercostal Space, heart is suspended on the pericardium support.A 1-2cm section of LCA (LCX) is separated near the first main diagnosis room branch.In LCX, insert the long 26-rule prong lead cathode electrode (Teflon coats, and 30-advises silver-coated copper wire) of 3-4mm and be close to intra-arterial arteries and veins placement (experiment finishes the back and confirms).Finish the stimulation loop by place anode in subcutaneous position.LCX placed around one adjustable plastics occludator on electrode zone.Near the Electromagnetic Flow probe (Carolina Medical electronic, King, the North Carolina state, the U.S.) that LCX placed around one pre-school is good negative electrode is measured coronary blood flow (CBF).After the 10-sLCX mechanical closure, adjusting occludator extremely observed 40-50% suppresses congested blood-flow reaction.Whole blood kinetics and ECG measure and use data-acquisition system (M3000 type, Modular Instruments, Malvern, PA, the U.S.) to write down and analyze.
Thrombosis and compound administration scheme
Logical 100 μ A unidirectional currents (DC) produce LCX inner membrance electric injury on the negative electrode.Electric current kept 60 minutes, and no matter whether vessel sealing all stops then.Spontaneous formation thrombosis is until LCX all closed if (increasing definite by zero CBF and S-T section).Aging closed thrombosis began to give chemical compound after 1 hour.Begin injection in 2 hours and give chemical compound of the present invention, dosage 0.5 and 1mg/kg/ hour, inject thrombosis simultaneously and generate agent (for example, organizing plasminogen activator, streptokinase, APSAC).Give behind the chemical compound to pour into again in 3 hours.Coronary artery after successful thromboembolism closure again is defined as zero CBF, and continues 〉=30 minutes.
Hematology and template bleeding time are measured
(Cell-Dyn 900 with blood analyser, Sequoia-Turner, Mount View, California, the U.S.) 40 μ l are added with blood sample (1 part of sodium citrate: 9 parts of blood) measure complete blood count, H﹠H value of sodium citrate (3.8%).Measure gum template bleeding time with a Simplate II bleeding time device (Organon Tekrika Durham, the North Carolina state, the U.S.).On upper left jaw of Canis familiaris L. or left gum of mandible, cut two horizontal cut with device.Each otch is that 3mm is wide and 2mm is dark.Cut the back and calculate bleeding time with stopwatch.When oozing out, goes blood with the suction of Cotton Gossypii pad.The template bleeding time is for cutting the time that openning stops to bleeding.The bleeding time that draw and give (0 minute) before the experimental compound, injected in 60 minutes, the experimental compound administration finishes (120 minutes) and experiment end.
All data are then determined significance with Student-Neuman-Kuelspost hoct test with one way analysis of variance (ANOVA).Repeated measure ANOVA is to determine the significant difference between time point in experiment.Data will have the difference on the statistics on P＜0.05 level at least.All values is meansigma methods ± SEM.The guideline of following U.S.'s pathology meeting of all experiments.This method further specify people such as being recorded in Jackson, cardiovascular pharmacology magazine (J.Cardiovasc.Pharmacol.), 21,587-599 (1993).
In the template bleeding time detects, formula I chemical compound of the present invention also 0.25,0.50 and 1.0mg/kghr down assessment template bleeding time detect.
The positive findings of above-mentioned arbitrary detection can confirm the practicality of The compounds of this invention.
Proof suppresses the detection of autoimmune disease
Detect 1
Press people such as Holmdahl, clinical experiment immunology (Clin.Exp.Immunol.), 70, method is carried out described in the 373-378 (1987) (being incorporated herein for referencial use).Approximately 4～30 female Mus cystovarians excisions in 8-10 age in week.Begin to give The compounds of this invention in experimental group castrating three weeks of back.Formula I compound administration carries out immunity with Mus II collagen type after one week.Mus is classified by the clinical order of severity of arthritis, referring to people such as Holmdahl, and rheumatoid arthritis, 29,106 (1986), be incorporated herein for referencial use.Collect serum, and analyze anti--II collagen type active antibodies.When experiment finishes, go up extracting spleen cell to determine the T cytoactive from Mus.
Determine that with the ELISA detection of routine the former albumen of anticol-II type antibody titer reduction can illustrate this activity.Carry out the synthetic T cell of quantitatively can assessing of DNA to the reactive reduction of II collagen type with the thymidine absorption, this II collagen type gives spleen T-cell by the cell that antigen produces.At last, the clinical order of severity of disease is assessed by erythema first symptom and one or more limb swelling every day.Clinical assessment is relevant with histological examination.
Detect 2
4～30 be only just of age any nutrition purposes, especially for feeding animals feedstuff of female Sprague-Dawley Mus and water.Experimental group is accepted formula I chemical compound, and all Mus generally accept the Mus rope, sees people such as Amason, Arch.Neurol., and 21,103-108 (1969) is hereby incorporated by.Mus is classified according to experimental immunity encephalomyelitis symptom.Medicine-feeding type I chemical compound is put to death Mus after about 3～7 weeks, and their vertebral lines take out and check.
Active ability by chemical compound inhibition EAE illustrates.
Detect 3
Use 5～50 Mus (MRL/Ipr and NZB).Evaluate parameter is: by the quantitative Anti-DNA antibody of ELISA, and time-to-live and nephridial tissue inspection.Give the Mus The compounds of this invention also with above-mentioned parameter evaluation progression of disease.
Detect 4
Select 5～15 women to do clinical research.After the womankind is amenorrhea, that is, amenorrhea is 6～12 months before on-test, and they suffer from the autoimmune disease of reveal any symptoms, but other aspect health.Because idiosyncrasy that these are sick and self awareness feature, research has the placebo group, that is, the women is divided into two groups, and wherein a winding is subjected to formula I chemical compound as active substance, and another winding is subjected to placebo.Experimental group women every day oral 50～200mg medicine.Treatment continues 3～12 months.Symptom quantity and degree to two groups are held accurate recording, latter stage these results are compared in research.The not only result between two group memberships relatively, and each patient's result also with begin one's study before each patient report symptom relatively.
The practicality of formula I chemical compound can be influenced by the positive of above-mentioned at least one detection and illustrates.
Detection to the ischemic myocardial protection of reperfusion injury
With ten female rabbits of 1 milligram of formula I compounds for treating and adult male rabbit.After 15 minutes, rabbit is anaesthetized and with closed 30 minutes of its coronary artery, is carried out perfusion again in 4 hours then.
Matched group is treated with excipient.
With blue dyestuff assessment deathtrap, tetrazolium dye assessment infarct area.With respect to matched group, it is effective to the myocardial ischemia that suppresses reperfusion injury that the area of infarct area reduces formula I chemical compound.
The test method that shows the testosterone of increase
Select the age to judge at 60 normal males of 62～75 years old, choice criteria is as follows:
Be fit to the person:
1, by the normal male category of big city life insurance tables (Metropolitan Life Insurance Table) (appendix 1), body weight is 90%～130% of a medium ideal body weight.
2, the generaI investigation serum testosterone is lower than 500ng/dl.
3, the serum prostate specific antigen is less than or equal to 4ng/ml.
4, the clinical prostate inspection is normal, and ultrasonic generaI investigation does not have suspicious prostate knot.
5, the past does not have great medical record in two years, for example angina pectoris, myocardial infarction or angioplasty, and no visceral cancer history or any time do not have prostatitis adenocarcinoma in 5 years.
6, in normal generaI investigation, comprise in the normal cardiopulmonary inspection no peripheral blood vessel or venule disease, or the situation of other systemic disease.
7, by the ruling laboratory report, the following must be in normal high limit or lower bound scope in 10%: CBC (complete blood count (cbc)) comprises hemoglobin, hematocrit and total WBC (numeration of leukocyte).
The person of being not suitable for:
1, smoking male.
2, there is the medical history of thromboembolism or lung inspection plug arbitrary time in the past.
3, on the whole the drink every day male of the ethanol that surpasses 2 units is equivalent to 2 glasss of wines, 2 bottled beers.
4, the electrocardiogram generaI investigation is clinical has obviously unusually.
Parallel design is taked in research, and two groups of 10 and the 40mg/ days dosage of matched group and formula I chemical compound compared for 14 weeks.People's random assortment is to matched group or chemical compound group.Per two weeks are measured testosterone levels, adopt RIA, and the Coat-a-Count test kit can have been bought from California, USA 90045, No. 5700 diagnostic products companies in the 96th western street, Los Angeles city (Diagnostic Products Co.).Compare with matched group, the testosterone levels statistics significantly improves and shows that formula I chemical compound is effective to increasing serum testosterone.

Claims (14)

1, a kind of inhibition is selected from the method for following pathological symptom: syndrome before and after the Alzheimer's disease, premenstrual syndrome, amenorrhea, thrombomodulin shortage, fibrosis of uterus, excessively activity of myeloperoxidase, thrombin too much, the infringement of perfusion again and the testosterone deficiency of autoimmune disease, myocardial ischemia, this method comprises to what suffer from described pathological symptom waits to control mammal effective dose formula I chemical compound and its optics and geometric isomer; With and the acceptable acid-addition salts of nontoxic pharmacology, N-oxide, ester and quaternary ammonium salt,
Figure A9710341500021
Wherein,
A is selected from CH 2And NR;
B, D and E independently are selected from CH and N;
Y is:
(a) phenyl is chosen wantonly and independently is selected from R by 1-3 4Substituent group replace;
(b) naphthyl is chosen wantonly and independently is selected from R by 1-3 4Substituent group replace;
(c) C 3-C 8Cycloalkyl is chosen wantonly and independently is selected from R by 1-2 4Substituent group replace;
(d) C 3-C 8Cycloalkenyl group is chosen wantonly and independently is selected from R by 1-2 4Substituent group replace;
(e) five-ring heterocycles, this ring contain and are selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
(f) hexa-member heterocycle, this ring contain and are selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
(g) condense the bicyclic system that forms by one five or hexa-member heterocycle and phenyl ring, described heterocycle contains and is selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace; Z 1For:
(a)-(CH 2) pW(CH 2) Q-；
(b)-O(CH 2) pCR 5R 6-；
(c)-O(CH 2) pW(CH 2) q；
(d)-OCHR 2CHR 3-; Or
(e)-SCHR 2CHR 3-; G is:
(a)-NR 7R 8；
(b)
Figure A9710341500031
Wherein, n is 0,1 or 2; M is 1,2 or 3; Z 2Be-NH-,-O-,-S-or-CH 2-; Choose wantonly on adjacent carbons and condense, choose wantonly and independently on carbon atom replaced, and choose that independence is selected from R on the N atom wantonly by 1-3 substituent group with one or two phenyl ring 4The chemical property suitable substituents replace; Or
(c) contain the Neoquess of 5～12 carbon atoms, or for bridge closes or for condensing, and optionally independently be selected from R 41～3 substituent group replace; Or
Z 1With the combination of G can be:
Figure A9710341500032
W is:
(a)-CH 2-；
(b)-CH=CH-; (c)-O-; (d)-NR 2-; (e)-S (O) n-; (f) (g)-CR 2(OH)-; (h)-CONR 2-; (i)-NR 2CO-; (j) Or (k)-C ≡ C-; R is hydrogen or C 1-C 6Alkyl; R 2And R 3Independently be: (a) hydrogen; Or (b) C 1-C 4Alkyl; R 4Be: (a) hydrogen; (b) halogen; (c) C 1-C 6Alkyl; (d) C 1-C 4Alkoxyl; (e) C 1-C 4Acyloxy; (f) C 1-C 4Alkyl sulfide; (g) C 1-C 4Alkyl sulphinyl; (h) C 1-C 4Alkyl sulphonyl; (i) hydroxyl (C 1-C 4) alkyl; (j) aryl (C 1-C 4) alkyl;
(k)-CO 2H；
(l)-CN；
(m)-CONHOR；
(n)-SO 2NHR；
(o)-NH 2；
(p) C 1-C 4Alkylamino;
(q) C 1-C 4Dialkylamino;
(r)-NHSO 2；
(s)-NO 2；
(t) aryl; Or
(u)-OH。
R 5And R 6Independent is C 1-C 8Alkyl or form C together 3-C 10Carbocyclic ring;
R 7And R 8Independently be:
(a) phenyl;
(b) saturated or undersaturated C 3-C 10Carbocyclic ring;
(c) contain and be selected from-O-,-N-and-S-in two heteroatomic C at the most 3-C 10Heterocycle;
(d)H；
(e) C 1-C 6Alkyl; Or
(f) and R 5Or R 6Form 3～8 yuan the azo-cycle that contains;
The R of linearity or annular form no matter 7And R 8, can independently be selected from C arbitrarily 1-C 6Three substituent groups at the most of alkyl, halogen, alkoxyl, hydroxyl and carboxyl replace;
R 7And R 8The ring that forms can be arbitrarily and phenyl ring condense;
E is 0,1 or 2;
M is 1,2 or 3;
N is 0,1 or 2;
P is 0,1,2 or 3;
Q is 0,1,2 or 3.
2, formula I chemical compound and its optics and geometric isomer with and the acceptable acid-addition salts of nontoxic pharmacology, N-oxide, ester and quaternary ammonium salt, suppress to be selected from application in the medicine of following disease in preparation: syndrome before and after Alzheimer's disease, premenstrual syndrome, the amenorrhea, thrombomodulin shortage, fibrosis of uterus, excessively activity of myeloperoxidase, thrombin too much, the infringement of perfusion again and the testosterone deficiency of autoimmune disease, myocardial ischemia
Figure A9710341500061
Wherein,
A is selected from CH 2And NR;
B, D and E independently are selected from CH and N;
Y is:
(a) phenyl is chosen wantonly and independently is selected from R by 1-3 4Substituent group replace;
(b) naphthyl is chosen wantonly and independently is selected from R by 1-3 4Substituent group replace;
(c) C 3-C 8Cycloalkyl is chosen wantonly and independently is selected from R by 1-2 4Substituent group replace;
(d) C 3-C 8Cycloalkenyl group is chosen wantonly and independently is selected from R by 1-2 4Substituent group replace;
(e) five-ring heterocycles, this ring contain and are selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
(f) hexa-member heterocycle, this ring contain and are selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
(g) condense the bicyclic system that forms by one five or hexa-member heterocycle and phenyl ring, described heterocycle contains and is selected from-O--NR 2-and-S (O) n-in two hetero atoms at the most, optional independently be selected from R by 1-3 4Substituent group replace;
Z 1For:
(a)-(CH 2) pW(CH 2) q-；
(b)-O(CH 2) pCR 5R 6-；
(c)-O(CH 2) pW(CH 2) q；
(d)-OCHR 2CHR 3-; Or
(e)-SCHR 2CHR 3-
G is: (a)-and NR 7R 8(b)
Figure A9710341500071
Wherein, n is 0,1 or 2; M is 1,2 or 3; Z 2Be-NH-,-O-,-S-or-CH 2-; Choose wantonly on adjacent carbons and condense, choose wantonly and independently on carbon atom replaced, and choose that independence is selected from R on the N atom wantonly by 1-3 substituent group with one or two phenyl ring 4The chemical property suitable substituents replace; Or
(c) contain the Neoquess of 5～12 carbon atoms, or for bridge closes or for condensing, and optionally independently be selected from R 41～3 substituent group replace; Or
Z 1With the combination of G can be: W is: (a)-and CH 2-; (b)-CH=CH-; (c)-O-; (d)-NR 2-; (e)-S (O) n-; (f)
Figure A9710341500073
(g)-CR 2(OH)-; (h)-CONR 2-; (i)-NR 2CO-; (j) Or
(k)-C ≡ C-; R is hydrogen or C 1-C 6Alkyl; R 2And R 3Independently be: (a) hydrogen; Or (b) C 1-C 4Alkyl; R 4Be: (a) hydrogen; (b) halogen; (c) C 1-C 6Alkyl; (d) C 1-C 4Alkoxyl; (e) C 1-C 4Acyloxy; (f) C 1-C 4Alkyl sulfide; (g) C 1-C 4Alkyl sulphinyl; (h) C 1-C 4Alkyl sulphonyl; (i) hydroxyl (C 1-C 4) alkyl; (j) aryl (C 1-C 4) alkyl; (k)-CO 2H; (l)-CN; (m)-CONHOR; (n)-SO 2NHR; (o)-NH 2(p) C 1-C 4Alkylamino; (q) C 1-C 4Dialkylamino; (r)-NHSO 2
(s)-NO 2；
(t) aryl; Or
(u)-OH。
R 5And R 6Independent is C 1-C 8Alkyl or form C together 3-C 10Carbocyclic ring;
R 7And R 8Independently be:
(a) phenyl;
(b) saturated or undersaturated C 3-C 10Carbocyclic ring;
(c) contain and be selected from-O-,-N-and-S-in two heteroatomic C at the most 3-C 10Heterocycle;
(d)H；
(e) C 1-C 6Alkyl; Or
(f) and R 5Or R 6Form 3～8 yuan the azo-cycle that contains;
The R of linearity or annular form no matter 7And R 8, can independently be selected from C arbitrarily 1-C 6Three substituent groups at the most of alkyl, halogen, alkoxyl, hydroxyl and carboxyl replace;
R 7And R 8The ring that forms can be arbitrarily and phenyl ring condense;
E is 0,1 or 2;
M is 1,2 or 3;
N is 0,1 or 2;
P is 0,1,2 or 3;
Q is 0,1,2 or 3.
3, the application of claim 1, formula I chemical compound wherein is a following formula: Wherein, G is
Figure A9710341500101
Or
4, the application of claim 2, formula I chemical compound wherein is selected from down group:
Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidines-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol;
(-)-cis-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol;
Cis-6-phenyl-5-[4-(2-pyrrolidine-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol;
Cis-1-[6 '-pyrrolidine ethyoxyl-3 '-pyridine radicals]-2-phenyl-6-hydroxyl-1,2,3, the 4-naphthane;
1-(4 '-the pyrrolidine ethoxyphenyl)-2-(4 " fluorophenyl)-6-hydroxyl-1,2,3, the 4-tetrahydroisoquinoline;
Cis-6-(4 '-hydroxyphenyl)-5-[4-(2-piperidines-1-base-ethyoxyl)-phenyl]-5,6,7,8-naphthane-2-alcohol; With
1-(4 '-the pyrrolidine ethoxyphenyl)-2-phenyl-6-hydroxyl-1,2,3, the 4-tetrahydroisoquinoline.
5, the application of claim 2, wherein said pathological symptom are Alzheimer's disease.
6, the application of claim 2, wherein said pathological symptom are that thrombomodulin lacks.
7, the application of claim 2, wherein said pathological symptom are fibrosis of uterus.
8, the application of claim 2, wherein said pathological symptom are excessive activity of myeloperoxidase.
9, the application of claim 2, wherein said pathological symptom are that thrombin is too much.
10, the application of claim 2, wherein said pathological symptom are autoimmune disease.
11, the application of claim 2, wherein said pathological symptom are the infringement of perfusion again of myocardial ischemia.
12, the application of claim 2, wherein said pathological symptom are the testosterone deficiency.
13, the application of claim 2, wherein said pathological symptom are premenstrual syndrome.
14, the application of claim 2, wherein said pathological symptom are syndrome before the amenorrhea.
CN97103415A 1996-02-28 1997-02-28 Method of treating conditions with estrogen agonists Pending CN1165655A (en)

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IL120267A (en) 2002-11-10
KR970061256A (en) 1997-09-12
AU1498097A (en) 1997-09-04
CA2198562A1 (en) 1997-08-28
PT792642E (en) 2001-12-28
AU703384B2 (en) 1999-03-25
ATE204475T1 (en) 2001-09-15
TW442286B (en) 2001-06-23
DE69706209T2 (en) 2001-12-06
MX9701605A (en) 1998-04-30
US5889042A (en) 1999-03-30
ZA971713B (en) 1998-08-27

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